ALUMINUM TOXICITY--CHELATOR IDENTIFICATION AND SAFETY

长期目标是确定口服有效的铝络合剂 对铝和动物的安全性有足够的选择性，以保证在 人类用于预防和治疗铝蓄积障碍。一个 理想的铝络合剂将克服去铁胺的局限性，即 缺乏口服疗效，其成本和毒性相对较高。阿尔 蓄积是由非肠道给药造成的， 肾功能受损者长期食用铝基磷酸盐粘结剂 以及产业工人暴露在铝烟雾中。铝在人体内的作用 阿尔茨海默氏症和其他痴呆症正在调查中 而且是有争议的。一种安全且持续有效的铝螯合剂可能会有所帮助 确定铝在这些疾病中的作用。该计划的具体目标是 目前的应用是测试系统可用性的假设， 铝络合剂的有效性和安全性与细胞的亲脂性有关 螯合剂和铝-螯合剂络合物导致铝从 储存地点，以安全地诱导铝消除和降低铝毒性。 3-羟基吡啶-4-酮的八个类似物，这是一个口服有效的金属家族 将对螯合剂进行研究。它们的亲脂性从下到上不等。 假设的理想范围。每种类似物的口服生物利用度 在兔体内被量化以确定两者之间的关系 亲油性和吸收率。这些类似物将进行单次剂量测试。 体内铝螯合活性的兔体内研究， 表现为血铝和胆汁或尿铝排出量增加。已选择 口服吸收的类似物会增加铝的排除量 给铝负荷的兔灌胃以确定其持续口服铝 重复使用后铝排出增加证明的螯合效果 治疗和降低组织铝含量。安全性和逆转铝诱导的能力 毒性将通过组织病理学、血液学和骨骼学进行评估 组织学和组织形态计量学测量。铝的专一性 将通过对选定的流体进行多元素分析来评估螯合作用 还有纸巾。疗效和安全性结果将与 亲脂性以确定其最佳亲脂性 3-羟基吡啶-4-酮。结果可能会识别出一些化合物 在人体上进行测试，将有力地指导未来的设计和选择 结构不同的化合物作为潜在的铝螯合剂。

The long-term goal is to identify orally effective aluminum chelators with sufficient selectivity for Al and safety in animals to warrant testing in humans for the prevention and treatment of Al accumulation disorders. An ideal Al chelator will overcome the limitations of desferrioxamine, namely lack of oral efficacy, its relatively high cost and toxicity. Al accumulation results from parenteral administration of pharmaceuticals, prolonged consumption of Al-based phosphate binders by the renally impaired and exposure of industrial workers to Al fumes. The role of Al in Alzheimer's disease and other dementing disorders is under investigation and is controversial. A safe Al chelator with continued efficacy may help determine the role of Al in these diseases. The specific aim of the present application is to test the hypothesis that systemic availability, efficacy and safety of Al chelators relates to the lipophilicity of the chelator and the Al-chelator complex results in Al mobilization from storage sites to safely induce Al elimination and reduce Al toxicity. Eight analogs of 3-hydroxypyridin-4-one, a family of orally effective metal chelators, will be studied. Their lipophilicity ranges from below to above the hypothesized ideal range. The oral bioavailability of each analog will be quantitated in rabbits to determine the relationship between lipophilicity and absorption. The analogs will be tested in a single dose iv study in Al-loaded rabbits to determine in vivo Al chelation activity, evidenced by increased serum Al and biliary or urinary Al output. Selected orally absorbed analogs that increase Al elimination will be repeatedly administered to Al-loaded rabbits to ascertain their continued oral Al chelation efficacy as evidenced by increased Al elimination after repeated treatment and decreased tissue Al. Safety and ability to reverse Al-induced toxicity will be assessed by histopathological, hematological and bone histological and histomorphometric measurements. Specificity of Al chelation will be assessed by multiple element analysis of selected fluids and tissues. Efficacy and safety results will be correlated to lipophilicity to identify the optimal lipophilicity of the 3-hydroxypyridin-4-ones. The results may identify compounds that warrant testing in humans and will strongly guide the future design and selection of structurally dissimilar compounds as potential Al chelators.